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On November 26, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval* to the first-ever precision medicine for cancer that was designed and developed specifically to target a genetic mutation in patients, regardless of the type of cancer and the body site where the tumor arose.

The treatment is known as Vitrakvi (larotrectinib, Bayer/Loxo) and is approved for the treatment of patients – both adult and pediatric – with advanced solid tumors (all cancers that are not blood-based like leukemia, lymphoma, and myeloma) that harbor a type of mutation known as an “NTRK gene-fusion.” This means that any patient who has a solid tumor, anywhere in the body, that tests positive for this mutation** can receive Vitrakvi and the treatment would be considered “on-label,” meaning it’s FDA approved to treat their tumor, and thus more likely to be covered by insurers***.

The approval is based on an integrated analysis of three clinical trials which enrolled pediatric, adolescent, and adult patients with 17 unique cancer diagnoses. Data from these trials showed that patients receiving Vitrakvi responded well to the treatment, with 75% seeing their tumors shrink, including 22% whose tumors completely disappeared. These results were also long-lasting, with many patients maintaining their response to the treatment for a year and counting. Vitrakvi was also deemed to be safe, with no patients having to discontinue the treatment due to adverse effects.

What does this mean for brain tumor patients?

NTRK gene fusions have been found in brain tumor patients with various gliomas. However, the percentage of glioma patients whose tumors do have NTRK gene fusion is very small – estimated to be only approximately one percent of patients. And though a small number of primary brain tumor patients participated in these Vitrakvi trials, they were enrolled in arms of the trials that tested for safety only, and none were part of the groups that were evaluated for the efficacy (effectiveness) of the treatment. Thus, there is little data from these three trials that speak to the potential efficacy of Vitrakvi specifically in brain tumor patients. Further, Vitrakvi was not designed to cross the blood-brain barrier, and thus there are unanswered questions about the drug’s potential ability to reach brain tumors.

That said, brain tumor patients who test positive for an NTRK gene-fusion, whose tumor has begun growing again after previous treatment, and where there are no additional treatment options, should likely be able to access Vitrakvi on-label. However, patients should consider that as of now**** there is no significant evidence from clinical trials that this particular drug will work as well for brain tumors patients as it did for the 75% of study patients who had their tumors shrink.

There is another drug in development, known as entrectnib (RXDX-101), that also is designed for patients with NTRK gene-fusions. This drug was designed specifically to cross the blood-brain barrier and has shown encouraging early results in treating cancers with the NTRK fusions, including brain tumors. This drug, which has been granted “breakthrough therapy” designation by the FDA, is now in a Phase II clinical trial (still open for enrollment) called STARTRK-2, sponsored by the pharmaceutical company Roche, which recently acquired entrectnib from the biotechnology company, Ignyta.

As is always the case, NBTS recommends patients discuss all of their treatment options – including standard of care, clinical trials, other investigational options, and potential off-label uses – with their medical team, and seek second opinions if desired.

Additional implications

Because Vitrakvi targets a specific genetic change found in some tumors, regardless of where they are located in the body, it is considered a “precisionmedicine.” As such, the only way to identify patients with NTRK gene-fusions is through tumorsequencing.

NBTS already recommends patients undergo tumor sequencing as part of their care, particularly in light of the updated World Health Organizationbrain tumor classification in 2016. There is some debate in the field about the utility of sequencing every cancer patient because of its cost, but this approval provides a stronger rationale that at least all patients with high-grade or recurrent brain tumors should undergo comprehensive tumor profiling. These tests are offered at most academic medical centers, tertiary care hospitals, and National Cancer Institute-designated cancer centers.

More about the Vitrakvi approval

Vitrakvi developed by Loxo Oncology, Inc. and Bayer after Bayer licensed the drug from Loxo (where it was originally known as LOXO-101).

Vitrakvi was originally granted breakthrough therapy designation in 2016.

In May 2018, the FDA granted priority review status.

A one-year’s supply of Vitrakvi is expected to carry a wholesale cost of approximately $394,000. However, according to statements Bayer has provided to media outlets, Bayer expects that for the majority of patients monthly out-of-pocket costs will be $20 or less. The company’s assistance programs will include co-pay assistance, and patients will receive the drug at no cost while patient insurance details are worked out. Bayer will provide refunds to payers and patients the cost of the first 60 days of treatment if the drug fails to show a clinical benefit in the first three months of treatment of a patient with the NTRK fusion. The same refunds go to government programs, including Medicare and Medicaid, as well as private insurers. “We recognize the fact that not all patients will respond to this treatment, and want to make sure that those patients who do not respond will not be responsible for the cost of the drug,” Kevin O’Leary, vice president for market access, pricing and contracting at Bayer, told The Cancer Letter.

More about NTRK gene-fusions

The NTRK family of genes includes three genes: NTRK1, NTRK2, and NTRK3. These genes provide the instructions (encode) for cells to produce a group of molecules called TRKs (Tropomyosin receptor kinase), which are enzymes. These TRK enzymes play a role in how cells grow and survive.

In NTRK gene-fusions, pieces of these genes fuse together abnormally with partners. The resulting fusion gene thus produces a hybrid version of the TRK enzymes. The altered enzymes now send incorrect signals in cells telling them to continue to grow when they should not be. The out-of-control growth of these cells drives tumor growth.

Drugs like Vitrakvi and entrectnib are able to target vulnerabilities in these hybrid enzymes and often, stop, reverse and/or kill tumor growth.

*The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measures that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval. Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market. [Source: FDA].

**The official approval language reads as: “For the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation are metastatic of where surgical resection is likely to result in severe morbidity, and have no satisfactory.”

***The FDA does not regulate the practice of medicine in the U.S., so technically any doctor can prescribe any treatment for any condition or patient if they believe it will benefit that individual, whether the treatment is FDA approved for that condition or not. This is called “off-label” use or prescribing. However, most health insurers, including Medicare and Medicaid, require scientific evidence – typically confirmed through FDA approval – that a medicine works for specific conditions for them to cover the treatment. Thus, often it can often be the case when receiving a medicine off-label that insurance will deny reimbursing that treatment.

****Vitrakvi is also still being tested in arms of both the ongoing National Cancer Institute’s MATCH and Pediatric MATCH trials.